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NICEATM ICCVAM
NICEATM ICCVAM National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods Interagency Coordinating Committee on the Validation of Alternative Methods Report and Recommendations from the NICEATM - ICCVAM International Workshop on Alternative Methods for Human and Veterinary Rabies Vaccine Testing Jodie Kulpa-Eddy, DVM, USDA Richard McFarland, MD, PhD, FDA Co-Chairs, ICCVAM Biologics Working Group SACATM Meeting September 6, 2012 National Institute of Environmental Health Sciences Research Triangle Park, NC 2008-2013 NICEATM-ICCVAM Five Year Plan Vaccine Potency and Safety Testing - One of ICCVAM’s highest priorities - Multiple agencies involved - Human vaccines: FDA, NIH-NIAID, DOD, DHS, BARDA, CDC - Veterinary vaccines: USDA, DOI, DHS, NIH (Zoonotic diseases) “NICEATM and ICCVAM will: - Evaluate alternative test methods and testing strategies for vaccine potency testing - Facilitate acceptance of adequately validated test methods and humane endpoints found to be sufficiently accurate and reliable.” http://iccvam.niehs.nih.gov/docs/5yearplan.htm ICCVAM 2 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Advance Alternative Test Methods and Strategies: Vaccines and Biologics Rationale for Priority - Vaccines/biologics accounts for majority of animals used for testing (2/3) Many animals experience significant unrelieved pain and distress Public Health Significance - Biologics include vaccines, blood and blood components, tissues, antibodies, and other substances used to treat or protect against disease in humans and animals http://iccvam.niehs.nih.gov/docs/5yrPlan/NICEATM5YR-Final.pdf 3 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare ICCVAM NICEATM Animals Used in Testing that Involves Unrelieved Pain and Distress (No Pain Relievers) Animals by Testing Type Reported to USDA (2010): Biologics and Vaccine Testing 57% (54,889) • 57% (54,889) of the animals reported to USDA that experience unrelieved pain and distress are used for testing Biologics and Vaccines Toxicity and Efficacy Testing 38% (37,108) • Estimated that 2 million animals used for testing that involves unrelieved pain and distress (U.S.) • Est. 95% of these are rats, mice, and birds (not reported to USDA) Research 5% (5,126) Data for all states with all animal data for Column E of APHIS Form 7023; USDA. 2010. Annual Report - Animal Usage by Fiscal Year. United States Department of Agriculture. Animal and Plant Health Inspection Service. Available at: http://www.aphis.usda.gov/animal_welfare/efoia/7023.shtml 4 Based on NICEATM review of Column E justifications posted by USDA. NICEATM-ICCVAM - Advancing Public Health and Animal Welfare ICCVAM NICEATM Animals Used for Testing by Major Categories (EU 2010) Production and QC of Medicines, Biologics, vaccines etc. Toxicity Testing 63% (1,788,000) 37% (1,044,000) Total EU annual animal use for testing: 2,832,000 Majority of Animal Use is for Testing Biologics and Vaccines Report on the Statistics on the Number of Animals used for Experimental and other Scientific Purposes in the Member States of the European Union COM(2010) 511 5 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare ICCVAM NICEATM NICEATM-ICCVAM International Workshop: Human and Veterinary Vaccine Potency and Safety Testing September 14-16, 2010 – Co-organizers included: - Workshop Output: - http://www.sciencedirect.com/science/article/pii/S1877282X11000245 6 EURL ECVAM, JaCVAM, Health Canada Nearly 200 scientists, 13 countries NICEATM-ICCVAM - Advancing Public Health and Animal Welfare Procedia in Vaccinology 5: 1-266 (2011) Recommendations for the implementation and use of alternative methods Priorities identified for future work needed to advance alternatives Enhanced International harmonization Conduct vaccine-specific workshop for priority areas: • Rabies (2011) • Leptospirosis (2012) • Pertussis vaccines (acellular) (2012) • Diphtheria and tetanus toxoids (2013planned) ICCVAM NICEATM NICEATM-ICCVAM International Workshop on Human and Veterinary Rabies Vaccine Testing October 2011: USDA Center for Veterinary Biologics Ames, IA Attended by over 80 human and veterinary rabies vaccine experts representing: - 14 countries Industry and academia Regulatory authorities and international organizations • FDA, USDA, NIAID, WHO, OIE, PEI (Germany), IVI (Switzerland), NVAL (Japan), AHVL (UK) and National Institute for Health Quality Control (Brazil) Rabies Workshop summary and discussion highlights are available at: http://iccvam.niehs.nih.gov/meetings/RabiesVaccWksp-2011/RabiesVaccWksp.htm ICCVAM 7 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Acknowledgements: ICCVAM Interagency Biologics Working Group U.S. Food and Drug Administration Center for Biologics Evaluation and Research • Richard McFarland, PhD, MD (Co-Chair) Center for Drug Evaluation and Research • Abigail Jacobs, PhD (CDER) Center for Food Safety and Nutrition • Suzanne Fitzpatrick, PhD, DABT (CFSAN) U.S. Department of Agriculture Jodie Kulpa-Eddy, DVM (Co-Chair) David Dusek, PhD Donna Gatewood, DVM Geetha Srinivas, DVM, PhD Centers for Disease Control and Prevention Susan Maslanka, PhD Department of Defense Department of Interior Tonie Rocke, PhD National Institute of Allergy and Infectious Diseases/NIH Suman Mukhopadhyay, PhD National Institute of Environmental Health Sciences/ NIH William Stokes, DVM, DACLAM Warren Casey, Ph. DABT Health Canada Liaisons Richard Isbrucker, PhD Michele Regimbald-Krnel, PhD EURL ECVAM Liaison Marlies Halder, DVM JaCVAM Liaison Hajime Kojima, PhD Leonard Smith, PhD Janet Skerry ICCVAM 8 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Acknowledgements: Organizing Committee BWG Members Subject Experts William Stokes, DVM, DACLAM NIEHS, USA Warren Casey, PhD, DABT NIEHS, USA Jodie Kulpa-Eddy, DVM (Co-Chair) USDA, USA Richard McFarland, MD, Ph.D. (Co-Chair) FDA, USA Suman Mukhopadhyay, PhD NIAID, USA Geetha Srinivas, DVM, PhD USDA, USA Marlies Halder, DVM EURL ECVAM, Italy Richard Isbrucker, PhD Health Canada, Canada Hajime Kojima, PhD JaCVAM, Japan Michele Regimbald-Krnel, PhD Health Canada, Canada 9 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare Donna Gatewood, DVM USDA, USA Robin Levis, PhD U.S. FDA, USA Charles Lewis, DVM USDA, USA Joseph Hermann, PhD USDA, USA Carmen Jungback, PhD Paul-Ehrlich-Institut, Germany Catherine Milne, PhD EDQM, UK Gayle Pulle, PhD Health Canada, Canada Mutsuyo Takayama-Ito, DVM, PhD National Institute of Infectious Diseases, Japan Maria Luz Pombo, PhD PAHO, USA Karen Brown, PhD Pair O Doc’s Consultants, USA Alexander Gaydamaka, DVM, PhD ICCVAM Merial/AHI, USA NICEATM Acknowledgements: Workshop Organizers and Co-Sponsors Organizers: - National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) - Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) - European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) - Japanese Center for the Validation of Alternative Methods (JaCVAM) - Health Canada Co-Sponsors - Center for Veterinary Biologics, USDA - International Alliance for Biological Standardization (IABS) - National Institute of Environmental Health Sciences (NIEHS) - National Toxicology Program (NTP) - Society of Toxicology (SOT) ICCVAM 10 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Rabies Workshop Objectives Review state of the science of available alternative methods; identify data gaps Develop implementation strategy to achieve regulatory acceptance, implementation, and use Evaluate available replacement in vitro assays for potency testing and process control parameters and assays for lot consistency Evaluate potential reduction and refinements to current in vivo test, where and when animal testing still necessary Rabies virus graphic utmb.edu 11 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare ICCVAM NICEATM Rabies Workshop Program Opening Plenary Session: - Non-Animal Methods and Strategies - Currently Available In Vivo Assays Development and Validation of a Serological Method Breakout Discussion Sessions: - 12 Antigen Quantification New Technologies Consistency of Manufacturing Parameters Current NIH Research on Improved Rabies Vaccines Reduction and Refinement Opportunities: - Public Health and Animal Health Perspectives US and International Regulatory Requirements Industry Perspectives In Vitro Antigen Quantification Methods Antibody Quantification (Serologic Methods) Refinement and Reduction Opportunities NICEATM-ICCVAM - Advancing Public Health and Animal Welfare ICCVAM NICEATM Workshop Rationale: Rabies Vaccine Potency Testing Public health and animal health1 - 15M people receive postexposure rabies prophylaxis treatment each year 70,000 human fatalities annually Dogs are dominant reservoir outside developed countries Regulatory requirements - Global use of mouse vaccinationchallenge test 50,000-70,000 mice used per year in US and EU for potency testing and release of human and veterinary rabies vaccines2 1Bouhry H, Dautry-Varsat A, Hotez PJ, Salomon J. 2010. Rabies, still neglected after 125 years of vaccinations. PLOS Neglect Trop D 4(11):e839. 2Bruckner L, Cussler K, Halder M, Barrat J, Castle P, Duchow K, et al. 2003. Three Rs approaches in the quality control of inactivated rabies vaccines. ECVAM Workshop Report 48. ATLA 31:429-454. 13 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare ICCVAM NICEATM Current In Vivo Potency Method NIH Challenge Test - Immunization of mice with multiple dilutions of vaccine - Intracerebral (IC) challenge ~14 days post immunization - Observed for 5-14 days post-challenge Two sources of pain and distress - IC challenge • Some laboratories use general anesthesia without any interference in test outcome - Inadequately protected mice demonstrate clinical signs of rabies (i.e. paralysis, paresis and convulsions) 6-9 days following challenge ICCVAM 14 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Current Status: Replacement (1) The rabies virus spike glycoprotein (G protein) is the primary rabies virus antigen shown to induce rabies virus neutralizing antibodies The natively folded G protein is virion-associated, trimeric and highly immunogenic. In vitro potency tests must be able to distinguish between the highly immunogenic (virion-associated, trimeric) and poorly immunogenic forms. Schematic diagram of a rabies virus particle. http://www.cdc.gov/rabies/transmission/virus.html) ICCVAM 15 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Current Status: Replacement (2) Japan has developed and used for 10 years an ELISA for potency release testing of a non-adjuvanted veterinary rabies vaccine. - Monoclonal antibody utilized which detects only the conformationally intact G protein. A similar test is used in many laboratories to quantitate the G protein content of in-process samples but not yet used as a potency release test for other products. ICCVAM 16 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Workshop Recommendations: Replacement (1) Non-adjuvanted human and veterinary rabies vaccines should be high priority for in vitro method product specific validation Manufacturers are encouraged to develop, validate, and implement in vitro antigen quantification methods to replace the NIH test NICEATM-ICCVAM developed a comprehensive list of available monoclonal antibodies for product specific testing and validation ICCVAM 17 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Refinement and Reduction Current Status: Serum Neutralization Test (SNT) Method used to detect and quantify antibodies in serum that neutralize Rabies virus SNT addresses Reduction and Refinement 3Rs goals by: - Reducing animal use per test vaccine by up to 10-fold Avoids pain and distress of IC challenge test Reduced cost and more time effective European Directorate for the Quality of Medicines and HealthCare (EDQM) international collaborative study of 13 laboratories from 10 countries, including the US (USDA)1 - Confirmed accuracy and interlaboratory transferability of SNT - SNT able to distinguish lots identified as sub-potent in IC challenge test - Group of Experts 15V recommended SNT for inclusion in revised Ph. Eur. Monograph 0451 (Approved April 2012) 1Kramer rabies 18 B, Bruckner l, Daas A, Milne C. 2010. Collaborative study for validation of a serological potency assay for vaccine (inactivated) for veterinary use. Parmeur Biol Scientific Notes 2: 37-55. NICEATM-ICCVAM - Advancing Public Health and Animal Welfare ICCVAM NICEATM SNT: Sufficiently Standardized for Product Specific Validation (2) Based on results of interlaboratory validation study and acceptance of the method in the Ph. Eur. Monograph 0451 for inactivated veterinary rabies vaccines, the SNT is considered sufficiently standardized to provide an alternative to the NIH challenge test. Therefore, veterinary rabies vaccine manufacturers in collaboration with regulatory authorities should: - Initiate product specific validation with SNT Validation should assess ability to identify subpotent lots Validation of the multi-dilution SNT should progress - To evaluate stability of test and reference vaccine lots To calibrate new standards To evaluate changes in the manufacturing process ICCVAM 19 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Workshop Recommendations: Reduction (1) Manufacturers and regulatory authorities should investigate reduction in number of mice used per dilution - Especially at higher and lower vaccine dilutions, and for vehicle, and positive control groups Human rabies vaccine manufacturers should review historical test data for justification to eliminate duplicate mouse potency testing Manufacturers should test multiple lots at the same time Regulatory authorities should establish criteria that could avoid duplicate potency testing upon vaccine importation ICCVAM 20 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Workshop Recommendations: Refinement (1) Regulatory agencies and global organizations should encourage: Immediate incorporation of humane endpoints Routine use of general anaesthesia for intracerebral injections • PEI Manuscript accepted in Biologicals (2012) – supported use of anesthesia for rabies potency testing Provision of analgesics to avoid or minimize post-procedural pain and distress - Recommendations contingent upon studies to determine no interference with the study outcome - Investigate use of SR analgesics to avoid or minimize pain and distress without interfering with study objectives ICCVAM 21 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Post-Workshop Implementation Actions for Veterinary Vaccines: Refinement (2) May 25, 2012: USDA CVB Notice 12-12: “Use of Humane Endpoints and Methods in Animal Testing of Biological Products” - 22 CVB policy describing humane endpoints to be used in animal challenge tests and use of anesthesia before and during intracerebral (IC) challenge • Animals exhibiting paresis, signs of paralysis, and/or convulsions must be humanely euthanized and considered as deaths • Firms strongly encouraged to use anesthesia for IC challenge of mice • Encourages use of analgesics in animal studies and potency testing, when no effect shown on study outcome USDA CVB Notice 12-12: http://www.aphis.usda.gov/animal_health/vet_biologics/publications/notice_12_12.pdf ICCVAM NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM NICEATM-ICCVAM International Workshop on Human and Veterinary Rabies Vaccine Potency Testing Summarizes invited speaker presentations, breakout group discussions and provides detailed recommendations for the validation, implementation and use of alternative methods. Detailed appendices include: • • • • Best Practices for the Rabies Challenge Test Serology Assay for Potency Testing of Inactivated Rabies Vaccines for Veterinary Use Rabies Virus Monoclonal Antibodies for Potency Testing Inactivated Rabies Vaccines Method of Production and Testing of Inactivated Veterinary Rabies Vaccines in Japan Workshop report available online 10 August 2012: http://dx.doi.org/10.1016/j.biologicals.2012.07.005 23 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare ICCVAM NICEATM Workshop Summary - Rabies Vaccine Potency Testing (1) Until in vitro replacements to the “NIH Challenge Test” are validated and implemented, the following are encouraged: Refinement - Anesthesia: should always be used for IC injections - Analgesics: should be provided to all mice; studies needed to ensure no interference with test objectives - Earlier humane endpoints: should be immediately incorporated in all testing regulations where not already included Reduction - Evaluate potential for fewer dilutions, fewer mice per dilution, and possible deletion of duplicate testing on each lot ICCVAM 24 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM Workshop Summary - Rabies Vaccine Potency Testing (2) Replacement of the “NIH Challenge Test” - Serological Methods: Serum Virus Neutralization Test (SNT) • Eliminates the need for challenge with live rabies virus: complete refinement • Sufficiently standardized per recent int’l study; manufacturers should conduct and submit product-specific validation studies, in consultation with regulatory agencies Complete animal replacement - In vitro antigen quantification methods: • Product specific validation should proceed with suitable monoclonal antibodies; must discriminate sub-potent lots • Requires monoclonal antibodies specific for the trimeric glycoprotein G ICCVAM 25 NICEATM-ICCVAM - Advancing Public Health and Animal Welfare NICEATM